The broad, long-term objectives of this proposal are the development of novel inhibitors that specifically prevent the interaction of nuclear receptors with their coactivating proteins through their NR box binding site and thus functionally block transcriptional activation by nuclear receptors. The Specific Aims of this proposal are 1) To use conformationally constrained peptide inhibitors of the interaction of the human thyroid receptor (hTRf3 1) with the glucocorticoid receptor interacting protein 1 (GRIP 1) to evaluate the structure-activity relationships of the individual leucine side chains of the LXXLL triad (NR box) of GRIP 1; 2) to design and synthesize sets of non-peptide compounds that mimic the side chain presentation of the LXXLL triad in order to establish viable scaffolds for discovery library synthesis that present their side chains in the correct geometry; 3) to synthesize libraries of non-peptide inhibitors and screen these to find specific inhibitors for nuclear receptor coactivator interactions; 4) to expand the biochemical model systems under consideration to include the estrogen receptor (ER), androgen receptor (AR), and peroxisome proliferator-activated receptor (PPAR) thus allowing the study of the specificity of inhibition of the nuclear receptor coactivator interactions; and 5) to optimize any active inhibitors of nuclear receptor function for maximal potency against particular receptors and selectivity among receptors. The health relatedness of this project is that the new method of inhibiting nuclear receptor function has the potential to provide new therapies for diseases mediated by nuclear receptors which include cancer, cardiovascular disease, diabetes, and osteoporosis - diseases currently treated with drugs based upon hormone structure. The research design is the use of molecular design and combinatorial chemistry to develop non-peptide inhibitors. The methods to be used are chemical synthesis, biochemical screening, structure determination, molecular design, and cellular biology evaluation of physiological effect.